Virtual Library
Start Your Search
H. Husain
Author of
-
+
MA08 - Treatment Monitoring in Advanced NSCLC (ID 386)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:R. Perez-Soler, T. Reungwetwattana
- Coordinates: 12/06/2016, 11:00 - 12:30, Lehar 3-4
-
+
MA08.11 - Monitoring the Emergence of EGFR T790M ctDNA in Urine from EGFR Mutated NSCLC Patients to Predict Response to 3rd Generation Anti-EGFR TKIs (ID 6342)
11:00 - 12:30 | Author(s): H. Husain
- Abstract
Background:
EGFR T790M mutation occurs in about half of EGFR mutated NSCLC patients with acquired EGFR-TKI resistance. It is currently unknown if switching therapy to a third generation anti-EGFR TKI based on circulating tumor DNA at first detection with urine is superior to switching therapy based on radiographic progression. Herein we demonstrate the identification of T790M in urine months before radiographic progression, patient responses when treated with an anti-EGFR third generation TKIs, clinical cutoffs that may be predictive of benefit, and a novel clinical trial to consider for treatment selection.
Methods:
From 2014 to 2016 a total of 42 patients with EGFR activating mutations were followed at UCSD Moores Cancer Center through multiple lines of therapy. 34 patients had serial urine collection every 4-6wks from time of first visit. Clinical progression was assessed with CT imaging performed every two months.
Results:
Among the 42 patients, 35 patients had metastatic disease (6 with intrathoracic M1a disease and 29 with distant metastasis M1b). Urine volume ranged from 30-100ml. Average time from first line TKI start to urine T790M was 15.7mos (CI 9.6-25.6), time from TKI start to radiographic progression was 21.9mos (CI 10.7-27.0), and time from urine T790M to radiographic progression was 3.6mos (CI 0.9-6.8). All patients with >30 copies/10[5] genome equivalents (GEq) of urine T790M had response to third generation TKIs. In patients who had urine EGFR T790M from 10-30 copies/10[5] GEq, three serial measurements in the 10-30 range predicted response. EGFR T790M copies of less than 10 copies/10[5] GEq did not predict response to third generation inhibitors.
Conclusion:
EGFR T790M can be identified in urine before radiographic progression and quantitative cut-offs can be predictive of response. We are testing this prospectively in a clinical trial with serial ctDNA analyses obtained for resistance monitoring for up to 24 months on first line TKI therapy. Patients who have urine detection of T790M (>30 copies or three serial collections with 10-30 copies/10[5] GEq) at 12 months and before progression are randomized to second line third generation TKI therapy or continuation of the first line therapy until progression. Patients with undetectable urinary T790M or <10 copies/10[5] GEq will continue on the first line therapy past 12 months until progression. Overall survival, progression free survival, and time to progression will be compared between cohorts to validate the early detection of T790M by urine ctDNA and understand the impact of an early switch in therapy based on ctDNA analyses.
Information from this presentation has been removed upon request of the author.
-
+
P2.06 - Poster Session with Presenters Present (ID 467)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Scientific Co-Operation/Research Groups (Clinical Trials in Progress should be submitted in this category)
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
-
+
P2.06-014 - Phase 2 Study of Glesatinib or Sitravatinib with Nivolumab in Non-Small Cell Lung Cancer (NSCLC) after Checkpoint Inhibitor Therapy (ID 4795)
14:30 - 15:45 | Author(s): H. Husain
- Abstract
Background:
Combination therapy with agents that target the molecular and cellular mechanisms of resistance to checkpoint inhibitor therapy (CIT) is a rational approach to restoring or improving the efficacy of CIT in patients with immunotherapy resistant NSCLC. Glesatinib, a tyrosine kinase inhibitor (TKI), which targets Axl, MER and MET RTKs expressed on macrophages and antigen-presenting-cells within the tumor microenvironment (TME), may reverse the immunosuppressive TME and enhance anti-tumor T and NK cell responses by enhancing antigen presentation and T cell effector function. Sitravatinib, also a TKI, which targets VEGFR2 and KIT as well as Axl, MER and MET, may further enhance anti-tumor activity by VEGFR2 and KIT inhibition mediated reduction of regulatory T cells and myeloid-derived suppressor cells (MDSCs). Given these pleiotropic immune activating effects, the combination of glesatinib or sitravatinib with nivolumab is a rational approach to restoring or enhancing the clinical activity of CIT in patients with immunotherapy resistant NSCLC.
Methods:
This open-label Phase 2 study evaluates the tolerability and clinical activity of the investigational agents, glesatinib or sitravatinib in combination with nivolumab in separate cohorts of patients with non-squamous NSCLC who have experienced progression of disease on or after treatment with CIT. The study begins with a limited dose escalation evaluation of each investigational agent in combination with nivolumab to determine the dose levels to be used in Phase 2. The primary objective is to assess the clinical activity of the combination regimens using the Objective Response Rate (ORR) by RECIST 1.1. Other objectives include safety, tolerability, pharmacokinetics and changes in circulating and tumor cell PD-L1, circulating and tumor infiltrating immune cell populations, cytokines and gene expression signatures. Enrollment into each Phase 2 treatment arm is stratified by prior outcome of CIT (e.g., clinical benefit versus progression of disease in ≤12 weeks). The investigational agents are administered orally in continuous regimens; nivolumab is administered intravenously, 3 mg/kg every 2 weeks. The sample sizes for the treatment arms are based on two-stage Simon Optimal Designs. Status: The US IND opened in June 2016.
Results:
Section not applicable
Conclusion:
Section not applicable
-
+
P3.02b - Poster Session with Presenters Present (ID 494)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
-
+
P3.02b-001 - Phase 1 Dose Escalation of PF-06747775 (EGFR-T790M Inhibitor) in Patients with Advanced EGFRm (Del 19 or L858R+/-T790M) NSCLC (ID 4747)
14:30 - 15:45 | Author(s): H. Husain
- Abstract
Background:
PF-06747775 (PF-7775) is a highly potent, selective third generation irreversible EGFR-TKI, effective against EGFR-TKI sensitizing and resistance (T790M) mutations in NSCLC cell lines; IC50s between 3-12 nM and 26X greater selectivity toward mutant vs. wild-type (WT)EGFR. This is the first report from an ongoing phase I, first in human multicenter study (NCT02349633) of PF-7775 in patients with metastatic EGFRm+ NSCLC.
Methods:
EGFRm+ NSCLC pts, with acquired resistance to EGFR-TKIs enrolled into dose escalation cohorts of PF-7775, orally once daily, beginning at 25 mg. Stable brain metastases were allowed. All pts were assessed for pharmacokinetics (PK), response to therapy, and adverse events (AEs). Prospective central T790M testing was optional for dose escalation cohorts, but is required in subsequent expansion cohorts. Plasma samples were collected from all patients for ctDNA analysis of EGFR mutations.
Results:
Dose escalation is complete. 26 patients enrolled in 7 dose levels (25-600 mg): 58% female, mean age 63.5 years, Asian/Caucasian 61%/34%, 14/25 T790M+. Dosing reached 600 mg and then was expanded at a lower dose for better long term tolerability. RECIST responses were observed at all dose levels. BOR is PR 11(42.3%; 5 T790M+), stable disease 6(23.1%; 4 T790M+), PD 2(7.7%: 1 T790M+), symptomatic deterioration 1(3.8%; 1 T790M+), and indeterminate 6(23.1%; 3 T790M+). The AE profile is very favorable as predicted from the large WT margin. No DLTs were observed. Grade 3 AEs were noted at > 150 mg (diarrhea {n=4, 15.4%} and skin toxicities {n=8, 30.8%}). Figure 1. Best Change from Baseline in Tumor Size (%) Figure 1 PK were generally dose-proportional at doses of 25-600 mg, with a median apparent t~1/2~ of 6 h (range 4-30).
Conclusion:
PF-7775 has demonstrated early signals of clinical activity and is well tolerated in EGFRm+ NSCLC pts with acquired resistance to EGFR-TKIs.
